Steroid diversification by multicomponent reactions

• Leslie Reguera,
• Cecilia I. Attorresi,
• Javier A. Ramírez and
• Daniel G. Rivera

Beilstein J. Org. Chem. 2019, 15, 1236–1256, doi:10.3762/bjoc.15.121

• based on the use of 17-ketosteroids and chlorotrimethylsilane (TMSCl) as catalyst, which enables the formation of the nucleophilic enolate that attacks either benzaldehyde or its urea imine derivative [39]. Varied ketosteroids were employed, including methylestrone 39, dehydroepiandrosterone acetate and

• presence of I2 as catalyst. The mechanism follows the initial formation of the imine compound between the aldehyde and the arylamine, followed by an imino-Diels–Alder reaction with the enolate generated from the ketosteroid. The reaction is highly regioselective for the enolization of the ketone, thus

Alkylation of lithiated dimethyl tartrate acetonide with unactivated alkyl halides and application to an asymmetric synthesis of the 2,8-dioxabicyclo[3.2.1]octane core of squalestatins/zaragozic acids

• Herman O. Sintim,
• Hamad H. Al Mamari,
• Hasanain A. A. Almohseni,
• Younes Fegheh-Hassanpour and
• David M. Hodgson

Beilstein J. Org. Chem. 2019, 15, 1194–1202, doi:10.3762/bjoc.15.116

• -dialkylated tartrates 34a–f can be co-produced in small amounts (9–14%) under these conditions, and likely arise from the achiral dienolate 36 of tartrate 7. Enolate oxidation and acetonide removal from γ-silyloxyalkyl iodide-derived alkylated tartrates 17 and 24 give ketones 21 and 26 and then Bamford

• (e.g., 7, Scheme 2) was originally reported by Seebach and co-workers for ‘activated’ (allylic, benzylic) alkyl halides [17][18][19]. If an alkylated tartrate 9 could be accessed from a silyloxy-substituted alkyl iodide 8 and subsequently oxidised (for example via a second tartrate enolate) with

• notable in showing that the intermediate ester enolate 14 possessed sufficient stability not to undergo significant β-elimination under conditions of its generation and its alkylation: slow addition of pre-cooled LDA (−70 °C) to a mixture of the acetonide and electrophile in THF/HMPA at −78 °C, followed

Switchable selectivity in Pd-catalyzed [3 + 2] annulations of γ-oxy-2-cycloalkenones with 3-oxoglutarates: C–C/C–C vs C–C/O–C bond formation

• Yang Liu,
• Julie Oble and
• Giovanni Poli

Beilstein J. Org. Chem. 2019, 15, 1107–1115, doi:10.3762/bjoc.15.107

• transient η2-alkene complex A (steps a and b). Deprotonation of the pro-nucleophile 1a by the counter-anion of the η3-allyl-Pd complex exchanges the benzoate for the enolate anion (step c) [50], and following C–C bond formation from the resulting anion-scrambled complex C leads to the Pd(0) complex D (step

Multicomponent reactions (MCRs): a useful access to the synthesis of benzo-fused γ-lactams

• Edorta Martínez de Marigorta,
• Jesús M. de Los Santos,
• Ana M. Ochoa de Retana,
• Javier Vicario and
• Francisco Palacios

Beilstein J. Org. Chem. 2019, 15, 1065–1085, doi:10.3762/bjoc.15.104

• ) and a subsequent addition of enolate 37 onto the aldehyde moiety in 33, with concomitant decarboxylation and cyclization to form a phthalide intermediate 38 (Scheme 10). Then, the known amine-substitution reaction would transform phthalide 38 into isoindolinone 36. A conceptually very similar

Synthesis of the polyketide section of seragamide A and related cyclodepsipeptides via Negishi cross coupling

• Jan Hendrik Lang and
• Thomas Lindel

Beilstein J. Org. Chem. 2019, 15, 577–583, doi:10.3762/bjoc.15.53

• , geodiamolides and seragamides, is reported. The key step is a Negishi cross coupling of (R)-(3-methoxy-2-methyl-3-oxopropyl)zinc(II) bromide and an (E)-iodoalkene that was synthesized via an aluminium ester enolate attack at (R)-propylene oxide. The overall synthesis comprises nine steps with an overall yield

• )-propylene oxide. The C4–C5 double bond would be formed by Corey–Fuchs reaction. Reaction of the aluminium enolate of tert-butyl propionate (9, Scheme 2) with (S)-propylene oxide had provided Taylor et al. with a mixture of diastereomers of α-methylated γ-hydroxyester 11 favouring the (2S,4S)-syn over the

Thiol-free chemoenzymatic synthesis of β-ketosulfides

• Adrián A. Heredia,
• Martín G. López-Vidal,
• Marcela Kurina-Sanz,
• Fabricio R. Bisogno and
• Alicia B. Peñéñory

Beilstein J. Org. Chem. 2019, 15, 378–387, doi:10.3762/bjoc.15.34

• formed, an enzyme-catalysed hydrolysis and protonation of the resulting enolate would render the title β-ketosulfide products. This strategy avoids the use of acidic or basic conditions for the hydrolysis of the ester moiety that, normally, result unsuitable for methylene active-containing products as β

Synthesis of nonracemic hydroxyglutamic acids

• Dorota G. Piotrowska,
• Iwona E. Głowacka,
• Andrzej E. Wróblewski and
• Liwia Lubowiecka

Beilstein J. Org. Chem. 2019, 15, 236–255, doi:10.3762/bjoc.15.22

• electrophilic hydroxylation at C4 When the lithium enolate of dimethyl N-Cbz-L-glutamate 63 was treated with Davis oxaziridine, an inseparable 9:1 mixture of diastereoisomers was formed with (2S,4S)-64 predominating (Scheme 16) [74]. For sodium and potassium enolates diastereoselectivity of the hydroxylation

• [86][87][88] or a Diels–Alder reaction using acylnitroso compounds [89]. However, when compared with these multistep approaches hydroxylation of pyroglutamic acid derivatives seems to be the simplest option. Treatment of the lithium enolate of benzyl N-Boc-pyroglutamate (S)-86 with Davis oxaziridine

• produced (2S,4R)-87 (Scheme 22) [90][91][92]. HPLC investigation of the reaction mixture showed that (2S,4S)-87 was not formed [90]. Stereospecific hydroxylation occurred on the opposite side to the benzyloxycarbonyl group, i.e., only re-face of the enolate was attacked for steric reasons. It is worth

Synthesis of functionalised β-keto amides by aminoacylation/domino fragmentation of β-enamino amides

• Pavel Yanev and
• Plamen Angelov

Beilstein J. Org. Chem. 2018, 14, 2602–2606, doi:10.3762/bjoc.14.238

• Pavel Yanev Plamen Angelov Department of Organic Chemistry, University of Plovdiv Paisii Hilendarski, 24 Tsar Asen Str., 4000 Plovdiv, Bulgaria 10.3762/bjoc.14.238 Abstract Ethylenediamine-derived β-enamino amides are used as equivalents of amide enolate synthons in C-acylation reactions with N

• necessitates either a double deprotonation to ambident 1,3-dianions [10] or proper masking of the amide functionality prior to deprotonation [11][12]. Consequently, there are very few published reagents that are synthetically equivalent to primary or secondary amide enolate synthons. With regard to acylation

• scope [21]. A contribution of ours in this area is the application of ethylenediamine-derived β-enamino amides as synthetic equivalents of primary and secondary amide enolate synthons in reactions with acid chlorides [22]. To extend the scope of the methodology, we now have explored the acylation of

Microwave-assisted synthesis of biologically relevant steroidal 17-exo-pyrazol-5'-ones from a norpregnene precursor by a side-chain elongation/heterocyclization sequence

• Gergő Mótyán,
• László Mérai,
• Márton Attila Kiss,
• Zsuzsanna Schelz,
• Izabella Sinka,
• István Zupkó and
• Éva Frank

Beilstein J. Org. Chem. 2018, 14, 2589–2596, doi:10.3762/bjoc.14.236

• magnesium enolate of malonic acid half ester, prepared in situ from potassium methyl malonate, MgCl2 and triethylamine in acetonitrile, was added [24][25]. The acylation of magnesium methyl malonate by the preformed imidazole 3 led to the desired bifunctional starting material 4 in good yield (79

• magnesium enolate. Although the presence of a C16–C17 double bond as in 4' is assumed to be beneficial for a P45017α-inhibitory effect, further transformations of this compound were abandoned because of the insufficient yield and its potential tendency to react with monosubstituted hydrazines – not only

Quinolines from the cyclocondensation of isatoic anhydride with ethyl acetoacetate: preparation of ethyl 4-hydroxy-2-methylquinoline-3-carboxylate and derivatives

• Nicholas G. Jentsch,
• Jared D. Hume,
• Emily B. Crull,
• Samer M. Beauti,
• Amy H. Pham,
• Julie A. Pigza,
• Jacques J. Kessl and
• Matthew G. Donahue

Beilstein J. Org. Chem. 2018, 14, 2529–2536, doi:10.3762/bjoc.14.229

• electrophiles are reacted with the sodium enolate of ethyl acetoacetate, generated from sodium hydroxide, in warm N,N-dimethylacetamide resulting in the formation of substituted quinolines. A degradation–build-up strategy of the ethyl ester at the 3-position allowed for the construction of the α-hydroxyacetic

• synthesis method through the one-pot acylation of ethyl acetoacetate with isatoic anhydrides followed by dehydrative intramolecular cyclization to access the desired quinoline scaffold 10 [18]. We replaced sodium hydride as the base required to generate the enolate of ethyl acetoacetate with sodium

• formation of the quinoline is shown in Scheme 5 [27]. After initial formation of the enolate of ethyl acetoacetate with sodium hydroxide, water is generated in the reaction mixture, which then serves as a proton transfer agent. The resulting sodium enolate regioselectively attacks the more electrophilic

Synthesis of a leopolic acid-inspired tetramic acid with antimicrobial activity against multidrug-resistant bacteria

• Luce Mattio,
• Loana Musso,
• Leonardo Scaglioni,
• Andrea Pinto,
• Piera Anna Martino and
• Sabrina Dallavalle

Beilstein J. Org. Chem. 2018, 14, 2482–2487, doi:10.3762/bjoc.14.224

• and the formation of an enolate, which was subsequently reacted with 1-iododecane and deprotected with ceric ammonium nitrate to afford derivatives 8a and 8b, respectively. Unfortunately, at this stage all attempts to decarboxylate compounds 8a and 8b failed [22]. To overcome the problem of

• -alkylation. Moreover, we selected a base containing potassium as a metal cation, which provides a greater electron density to the nucleophilic enolate, thus favouring O-alkylation. Satisfyingly, O-selective alkylation of compound 10 was achieved by deprotonation with KHMDS followed by alkylation with benzyl

Synergistic approach to polycycles through Suzuki–Miyaura cross coupling and metathesis as key steps

• Sambasivarao Kotha,
• Milind Meshram and
• Chandravathi Chakkapalli

Beilstein J. Org. Chem. 2018, 14, 2468–2481, doi:10.3762/bjoc.14.223

• , compound 50 was treated with KHMDS in THF at −78 °C to produce enolate 51. Further, it was reacted with diphenyl chlorophosphate to generate vinyl phosphate 52, which was subjected to SM coupling in the presence of different 2-formylboronic acids 53 with the aid of the Pd(PPh3)4 catalyst to provide the

Synthesis of eunicellane-type bicycles embedding a 1,3-cyclohexadiene moiety

• Alex Frichert,
• Peter G. Jones and
• Thomas Lindel

Beilstein J. Org. Chem. 2018, 14, 2461–2467, doi:10.3762/bjoc.14.222

• if there are examples, where this was not the case [21][22]. Access to partially unsaturated eunicellane systems could also be of interest for studies on biosynthesis and chemical interconversion [7][10]. Results and Discussion Dihydrocarvone 9 was converted to the enolate and quenched with ethyl

Hydroarylations by cobalt-catalyzed C–H activation

• Rajagopal Santhoshkumar and
• Chien-Hong Cheng

Beilstein J. Org. Chem. 2018, 14, 2266–2288, doi:10.3762/bjoc.14.202

• forms cobalt enolate J2, which converts into J3 by the addition of aldehyde via a chair transition state in a diastereoselective manner. Finally, protonolysis affords product 62 and regenerates the active Co(III)Cp* catalyst for the next cycle. Later, Li et al. reported a Co(III)-catalyzed

Studies towards the synthesis of hyperireflexolide A

• G. Hari Mangeswara Rao

Beilstein J. Org. Chem. 2018, 14, 2106–2111, doi:10.3762/bjoc.14.185

• of the proposed synthetic sequence. Future studies will include the stereoselective epoxidation of 11 followed by opening of the epoxide and lactonization or 1,4-nucleophilic addition to the α,β-unsaturated ketone 11 followed by epoxidation of the resulted enolate with subsequent lactonization to

Hypervalent organoiodine compounds: from reagents to valuable building blocks in synthesis

• Gwendal Grelier,
• Benjamin Darses and
• Philippe Dauban

Beilstein J. Org. Chem. 2018, 14, 1508–1528, doi:10.3762/bjoc.14.128

• supported by DFT calculation have led to propose that the rate-determining step of the process would be the ligand exchange between TFA and the O-enolate (Scheme 41) [79]. The resulting cationic intermediate 88 could rapidly evolve through a [3,3] rearrangement. Even though the C-enolate 89 is more stable

Recent applications of chiral calixarenes in asymmetric catalysis

• Mustafa Durmaz,
• Erkan Halay and
• Selahattin Bozkurt

Beilstein J. Org. Chem. 2018, 14, 1389–1412, doi:10.3762/bjoc.14.117

• sodium cation plays an important role in making the sodium enolate soluble in organic phase and this leads to enantiofacial differentiation in the transition state [39]. Just recently, Neri et al. utilized the cation recognition abilities of calixarene-amides in phase-transfer catalysis [40]. Seven

• through the enolate mechanism and complete noncovalent catalysis still needs further investigation. Biginelli reaction The catalysts 69f–j (Figure 8) were successfully applied to the enantioselective multicomponent Biginelli reaction of benzaldehyde, ethyl acetoacetate and urea [68]. The results show that

A survey of chiral hypervalent iodine reagents in asymmetric synthesis

• Soumen Ghosh,
• Suman Pradhan and
• Indranil Chatterjee

Beilstein J. Org. Chem. 2018, 14, 1244–1262, doi:10.3762/bjoc.14.107

• for the asymmetric α-oxygenation of carbonyls. Nucleophilic attack of the oxygen nucleophile to the intermediate 100 or alternatively a reaction pathway through O-enolate intermediate 101 can explain the desired product formation. In 2014, Kita and Shibata reported a catalytic, enantioselective

• the enolate intermediate 111 followed by the generation of a C–C bond via conjugate addition delivered intermediate carbene 113. A 1,2-hydrogen shift led to the formation of products 108 with enantioselectivities up to 79% (Scheme 24). Later, Maruoka et al. improved the enantioselectivity up to 95% ee

Cross-coupling of dissimilar ketone enolates via enolonium species to afford non-symmetrical 1,4-diketones

• Keshaba N. Parida,
• Gulab K. Pathe,
• Shimon Maksymenko and
• Alex M. Szpilman

Beilstein J. Org. Chem. 2018, 14, 992–997, doi:10.3762/bjoc.14.84

• lithium enolate followed by a second SET step to complete the transformation (Scheme 1a) [16][17]. A different approach, developed by Maulide, relies on the highly efficient umpolung of amides into enolonium species using triflic anhydride, a pyridine base and pyridine N-oxides (Scheme 1b). These

• = H) to afford the 1,4-diketone 7 in 71% yield (Scheme 2) [31]. We therefore focused on identifying the minimum amount of the second enolate that would lead to optimal yields and found that as little as 1.2–1.4 equiv provided the desired 1,4-diketones in acceptable yields without the need for a large

• excess of the second coupling partner (Scheme 2). Since the two coupling partners are both trimethylsilyl enol ethers, an advantage of this method is that the optimization of the coupling of a given enolate pair may be investigated by simply reversing the order of addition. In general, the major

Syn-selective silicon Mukaiyama-type aldol reactions of (pentafluoro-λ⁶-sulfanyl)acetic acid esters with aldehydes

• Anna-Lena Dreier,
• Andrej V. Matsnev,
• Joseph S. Thrasher and
• Günter Haufe

Beilstein J. Org. Chem. 2018, 14, 373–380, doi:10.3762/bjoc.14.25

• : aldol reaction; ester enolate; fluorine; SF5 compounds; stereochemistry; Introduction The classical acid- or base-catalyzed directed cross aldol reaction of an aldehyde and an enolizable second carbonyl compound is one of the most powerful and reliable carbon–carbon bond-forming transformations in

• silylacetals) 5 in the aldol reactions (Scheme 2). From this enolate, two transition states A and B can be formed for the aldol reactions. B should be less favored due to the steric (and may be also electronic) repulsion of the aryl and the SF5 groups. Consequently, the syn-products resulting from transition

• reaction (see above), the nucleophilic attack of the silicon enolate (in our case the ketene silylacetal) at the TiCl4-activated aldehyde results in the formation of intermediate 6. Under the influence of the electron-donating substituent, the elimination of titanium oxide dichloride (Ti(O)Cl2) is favored

Recent developments in the asymmetric Reformatsky-type reaction

• Hélène Pellissier

Beilstein J. Org. Chem. 2018, 14, 325–344, doi:10.3762/bjoc.14.21

• . The stereochemistry of aza-Reformatsky reactions involving N-sulfinyl ketimines is generally explained through a six-membered transition state with the zinc coordinated to the sulfinyl oxygen atom and the enolate carbanion to the imino carbon atom. The other substituents accommodate in order to

• complex H. A subsequent addition of another molecule of BrZnCH2CO2Et to this complex results in the formation of complex I. In complex I, the double bond of the zinc enolate attacks the carbonyl group of the aldehyde providing compound J which led to the final product 50 under acidic work-up conditions

• ). Finally, good to excellent enantioselectivities (76–94% ee) combined to moderate to quantitative yields (45–99%) were reported by Matsubara and Haraguchi in the enantioselective Reformatsky reaction of aldehydes 48b–e,g–i,r–w with enolate equivalent 55 prepared from phenyl isocyanate 56 and CH2(ZnI)2 in

One-pot sequential synthesis of tetrasubstituted thiophenes via sulfur ylide-like intermediates

• Jun Ki Kim,
• Hwan Jung Lim,
• Kyung Chae Jeong and
• Seong Jun Park

Beilstein J. Org. Chem. 2018, 14, 243–252, doi:10.3762/bjoc.14.16

• to excellent yields (68% and 81%). However, a CF3 substituent, which is electron-withdrawing and might promote the keto form, provided the desired compound 8al in a low yield (14%). When the enolate was derived from 3-oxo-3-phenylpropanenitrile, 3-cyano-4-phenylthiophene 8am was obtained in a low

Gram-scale preparation of negative-type liquid crystals with a CF₂CF₂-carbocycle unit via an improved short-step synthetic protocol

• Tatsuya Kumon,
• Shohei Hashishita,
• Takumi Kida,
• Shigeyuki Yamada,
• Takashi Ishihara and
• Tsutomu Konno

Beilstein J. Org. Chem. 2018, 14, 148–154, doi:10.3762/bjoc.14.10

• addition reaction, a Michael addition reaction, giving rise to the corresponding magnesium enolate Int-L. The subsequent hydrolysis of Int-L then leads to the γ-hydroxyketone 8a', which easily tautomerizes into the more stable 5-membered hemiacetal 8a. From the above insight into the reaction mechanism, if

Volatiles from the tropical ascomycete Daldinia clavata (Hypoxylaceae, Xylariales)

• Tao Wang,
• Kathrin I. Mohr,
• Marc Stadler and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2018, 14, 135–147, doi:10.3762/bjoc.14.9

• from an α-cleavage next to the alcohol function. To verify this structural proposal for 11a, racemic 2-methylbutanal (18) was reacted in an aldol addition with the enolate anion of pentan-3-one (23) which produced a racemic mixture of all four diastereomers 11a–d (Scheme 4). All eight stereoisomers of

Vinylphosphonium and 2-aminovinylphosphonium salts – preparation and applications in organic synthesis

• Anna Kuźnik,
• Roman Mazurkiewicz and
• Beata Fryczkowska

Beilstein J. Org. Chem. 2017, 13, 2710–2738, doi:10.3762/bjoc.13.269

• hydride to give the expected ylides 51. A subsequent intramolecular attack of the ylidic carbon atom on the carbonyl group in the Wittig reaction provided 5- or 6-membered alkenes 52 in yields of 51–69% (Scheme 35) [3]. Another example of the use of the enolate anion as a carbon nucleophilic agent was

• reported by Fuchs, who obtained 1,3-cyclohexadienes 54 by reaction of 1,3-butadienyltriphenylphosphonium bromide with enolate anions 53 derived from aldehydes or ketones in yields of 35–57% (Scheme 36). The nucleophilic attack here was directed at position 4 of the diene [11]. Hewson and MacPherson

• of cyclic alkenes in the intramolecular Wittig reaction from vinylphosphonium bromide and ketoesters as precursors of carbon nucleophiles. Synthesis of 1,3-cyclohexadienes by reaction of 1,3-butadienyltriphenylphosphonium bromide with enolate anions. Synthesis of bicyclo[3.3.0]octenes by reaction of